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Fibronectin Type III Domain Containing 4 attenuates hyperlipidemia-induced insulin resistance via suppression of inflammation and ER stress through HO-1 expression in adipocytes.
Biochem Biophys Res Commun. 2018 07 07; 502(1):129-136.BB

Abstract

Although Fibronectin Type III Domain Containing 4 (FNDC4) has been reported to be involved in the modulation of inflammation in macrophages, its effects on inflammation and insulin resistance in adipose tissue are unknown. In the current study, we investigated the effects of FNDC4 on hyperlipidemia-mediated endoplasmic reticulum (ER) stress, inflammation, and insulin resistance in adipocytes via the AMP-activated protein kinase (AMPK)/heme oxygenase-1 (HO-1)-mediated pathway. Hyperlipidemia-induced nuclear factor κB (NFκB), inhibitory κBα (IκBα) phosphorylation, and pro-inflammatory cytokines such as TNFα and MCP-1 were markedly mitigated by FNDC4. Furthermore, FNDC4 treatment attenuated impaired insulin signaling in palmitate-treated differentiated 3T3-L1 cells and in subcutaneous adipose tissue of HFD-fed mice. FNDC4 administration ameliorated glucose intolerance and reduced HFD-induced body weight gain in mice. However, FNDC4 treatment did not affect calorie intake. Additionally, treatment with FNDC4 attenuated hyperlipidemia-induced phosphorylation or expression of ER stress markers such as IRE-1, eIF2α, and CHOP in 3T3-L1 adipocytes and in subcutaneous adipose tissue of mice. FNDC4 treatment stimulated AMPK phosphorylation and HO-1 expression in 3T3-L1 adipocytes and in subcutaneous adipose tissue of mice. siRNA-mediated suppression of AMPK and HO-1 abrogated the suppressive effects of FNDC4 on palmitate-induced ER stress, inflammation, and insulin resistance. In conclusion, our results show that FNDC4 ameliorates insulin resistance via AMPK/HO-1-mediated suppression of inflammation and ER stress, indicating that FNDC4 may be a novel therapeutic agent for treating insulin resistance and type 2 diabetes.

Authors+Show Affiliations

Department of Biotechnology, Yonsei University, Seoul, South Korea.Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA.Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.Research Administration Team, Seoul National University Bundang Hospital, Seongnam, South Korea. Electronic address: ohayo2030@hanmail.net.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29787756

Citation

Lee, Wonjae, et al. "Fibronectin Type III Domain Containing 4 Attenuates Hyperlipidemia-induced Insulin Resistance Via Suppression of Inflammation and ER Stress Through HO-1 Expression in Adipocytes." Biochemical and Biophysical Research Communications, vol. 502, no. 1, 2018, pp. 129-136.
Lee W, Yun S, Choi GH, et al. Fibronectin Type III Domain Containing 4 attenuates hyperlipidemia-induced insulin resistance via suppression of inflammation and ER stress through HO-1 expression in adipocytes. Biochem Biophys Res Commun. 2018;502(1):129-136.
Lee, W., Yun, S., Choi, G. H., & Jung, T. W. (2018). Fibronectin Type III Domain Containing 4 attenuates hyperlipidemia-induced insulin resistance via suppression of inflammation and ER stress through HO-1 expression in adipocytes. Biochemical and Biophysical Research Communications, 502(1), 129-136. https://doi.org/10.1016/j.bbrc.2018.05.133
Lee W, et al. Fibronectin Type III Domain Containing 4 Attenuates Hyperlipidemia-induced Insulin Resistance Via Suppression of Inflammation and ER Stress Through HO-1 Expression in Adipocytes. Biochem Biophys Res Commun. 2018 07 7;502(1):129-136. PubMed PMID: 29787756.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fibronectin Type III Domain Containing 4 attenuates hyperlipidemia-induced insulin resistance via suppression of inflammation and ER stress through HO-1 expression in adipocytes. AU - Lee,Wonjae, AU - Yun,Subin, AU - Choi,Geum Hee, AU - Jung,Tae Woo, Y1 - 2018/05/24/ PY - 2018/05/16/received PY - 2018/05/18/accepted PY - 2018/5/23/pubmed PY - 2018/11/6/medline PY - 2018/5/23/entrez KW - AMPK KW - Adipocyte KW - FNDC4 KW - HO-1 KW - Inflammation KW - Insulin resistance SP - 129 EP - 136 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 502 IS - 1 N2 - Although Fibronectin Type III Domain Containing 4 (FNDC4) has been reported to be involved in the modulation of inflammation in macrophages, its effects on inflammation and insulin resistance in adipose tissue are unknown. In the current study, we investigated the effects of FNDC4 on hyperlipidemia-mediated endoplasmic reticulum (ER) stress, inflammation, and insulin resistance in adipocytes via the AMP-activated protein kinase (AMPK)/heme oxygenase-1 (HO-1)-mediated pathway. Hyperlipidemia-induced nuclear factor κB (NFκB), inhibitory κBα (IκBα) phosphorylation, and pro-inflammatory cytokines such as TNFα and MCP-1 were markedly mitigated by FNDC4. Furthermore, FNDC4 treatment attenuated impaired insulin signaling in palmitate-treated differentiated 3T3-L1 cells and in subcutaneous adipose tissue of HFD-fed mice. FNDC4 administration ameliorated glucose intolerance and reduced HFD-induced body weight gain in mice. However, FNDC4 treatment did not affect calorie intake. Additionally, treatment with FNDC4 attenuated hyperlipidemia-induced phosphorylation or expression of ER stress markers such as IRE-1, eIF2α, and CHOP in 3T3-L1 adipocytes and in subcutaneous adipose tissue of mice. FNDC4 treatment stimulated AMPK phosphorylation and HO-1 expression in 3T3-L1 adipocytes and in subcutaneous adipose tissue of mice. siRNA-mediated suppression of AMPK and HO-1 abrogated the suppressive effects of FNDC4 on palmitate-induced ER stress, inflammation, and insulin resistance. In conclusion, our results show that FNDC4 ameliorates insulin resistance via AMPK/HO-1-mediated suppression of inflammation and ER stress, indicating that FNDC4 may be a novel therapeutic agent for treating insulin resistance and type 2 diabetes. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/29787756/Fibronectin_Type_III_Domain_Containing_4_attenuates_hyperlipidemia_induced_insulin_resistance_via_suppression_of_inflammation_and_ER_stress_through_HO_1_expression_in_adipocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(18)31202-6 DB - PRIME DP - Unbound Medicine ER -